Weighted gene co-expression network analysis to identify key modules and hub genes associated with paucigranulocytic asthma

Abstract

Background Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Methods Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein–protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Results Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Conclusions Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA.

IL18R1-Related Molecules as Biomarkers for Asthma Severity and Prognostic Markers for Idiopathic Pulmonary Fibrosis

“…We also explored the relationship between IL18R1 expression and airway inflammatory subtypes, which correlated closely with the response to inhaled glucocorticoid therapy. 24 We did not find any differences in IL18R1 expression across the airway inflammatory infiltration subtypes, even after adjusting for asthma severity (Figure 4C−E,H,I). The scRNA results showed that IL18R1 was predominantly expressed in MCs.…”

Delineating asthma according to inflammation phenotypes with a focus on paucigranulocytic asthma

“…Further studies showed that this 6 gene expression signature discriminated inflammatory phenotypes in individuals with more severe asthma and in 132 individuals with stable COPD [58,59] . In another transcriptomic analysis, six hub genes central to the PGA phenotype were identified from among 449 differentially expressed genes and were validated in a separate dataset: ADCY2 , CXCL1 , FPRL1 , GPR109B , GPR109A , and ADCY3 [60] . Nearly all of these hub genes are involved in the regulation of immune and inflammatory processes, so their further study may help to explain the weak inflammatory response in PGA.…”

“…[58,59] In another transcriptomic analysis, six hub genes central to the PGA phenotype were identified from among 449 differentially expressed genes and were validated in a separate dataset: ADCY2, CXCL1, FPRL1, GPR109B, GPR109A, and ADCY3. [60] Nearly all of these hub genes are involved in the regulation of immune and inflammatory processes, so their further study may help to explain the weak inflammatory response in PGA. In addition, in the U-BIOPRED severe asthma cohort study, the expression of IL18R1, IL1R2, IRAK3, and NLRP3 was lower in PGA than in the other inflammatory phenotypes; conversely, the expression of NLRP1, NLRC4, and NOD2 was higher in NA and MGA than in EA and PGA.…”

Paucigranulocytic Asthma: Potential Pathogenetic Mechanisms, Clinical Features and Therapeutic Management

“…Intrinsic abnormalities in the function of structural cells (such as epithelial cells, smooth muscle cells, vessels and neuronic cells) seem to be pivotal, and these cells seem to orchestrate and preserve airway inflammation [ 19 ] by secreting several paracrine or autocrine factors, which results in the modulation of cellular functions such as agonist-induced shortening, secretion and migration [ 20 ]. Li et al have demonstrated a different gene expression pattern in PGA with moderate discrimination ability, suggesting a decreased immune cell infiltration and function and further supporting the low intensity of the inflammatory process in PGA [ 21 ]. In this study, the genes most relevant to PGA that were detected were ADCY2 , CXCL1 , FPRL1 , GPR109B , GPR109A and ADCY3 , with earlier studies suggesting that ADCY3 upregulation is related to the suppressed function of dendritic cells [ 22 ], whereas the down-regulation of the other five genes has been shown to decrease chemotaxis and immune cell migration to the inflammatory sites [ 23 , 24 , 25 ].…”